Background: Isoliquiritigenin (ISL), a natural compound extracted from licorice, has chemopreventive and antitumor activities. The purpose of this study was to investigate the anticancer effect of ISL on human oral squamous cell carcinoma (OSCC). Methods: The anti-OSCC effects of ISL were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, flow cytometry, reverse transcription-polymerase chain reaction, Western blotting, promoter activity, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, malignant phenotype analysis, microRNA, and xenografting. Results: ISL induced OSCC cell cycle G2/M phase arrest, apoptosis, and DNA damage. However, the DNA repair-associated ataxia telangiectasia mutated (ATM) and phospho-ATM were downregulated, ATM mRNA remained unchanged, and the downstream signals were inhibited. ATM recovered when the caspase activity was blocked by Z-DVED-FMK. A low dose of ISL inhibited OSCC malignancy in vitro and reduced the tumor size in vivo. Conclusion: ATM was cleaved by ISL-activated caspase, thus inhibiting DNA repair in OSCC cells. Therefore, ISL is a promising chemopreventive agent against oral cancer.
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